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Enamine-Based Aldol Organocatalysis in Water Are They Really УAll WetФ.

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DOI: 10.1002/ange.200601392
Enamine-Based Aldol Organocatalysis in Water:
Are They Really “All Wet”?**
Andrew P. Brogan, Tobin J. Dickerson,* and Kim D. Janda*
aldol reaction · asymmetric catalysis ·
green chemistry · organocatalysis
rganocatalysis is a burgeoning field
of organic synthesis that employs substoichiometric amounts of an organic
compound to accelerate a reaction.[1, 2]
Recent advances in organocatalysis include a wide range of reactions and
often enable asymmetric induction in
organic solvents. In particular, the aldol
reaction is a key C C bond-forming
reaction that has tremendous synthetic
utility and is often the platform of choice
to examine new organocatalysts. Nature
has perfected the stereospecific aldol
reaction by using aldolase enzymes.
While these enzymes have synthetic
utility, they are limited by the lack of
large-scale compatibility and typically
do not have broad substrate recognition.
There are several examples of smallmolecule (MW<600)-organocatalyzed
aldol reactions that are capable of
asymmetric induction in organic solvents.[1, 2] However, from a green chemistry perspective, the use of water instead
of organic solvent is preferred to decrease environmental contamination.
Therefore, given the synthetic utility of
the asymmetric aldol reaction, there is
growing interest in the identification of
organocatalysts that are capable of efficiently performing this reaction in water. In this context, we note that the first
de novo tailored aqueous organocatalysts with high enantioselectivities were
catalytic antibodies.[3–5] The importance
and utility of these biomacromolecular
catalysts cannot be understated, however, alternative small-molecule-organocatalyzed reactions in water with
sufficient asymmetric induction would
have immense synthetic utility.
Two recent studies, one by Hayashi
et al.[6] (catalysts 1–4) and the other by
Barbas and co-workers[7] (catalysts 5–6),
described asymmetric small-molecule
amine catalysts that were proposed to
utilize enamine intermediates in water
(Figure 1). Reports of small-molecule
enamine-based aldol catalysis in water
are not limited to these publications and
have been scattered throughout the
literature over the last several years.[8–12]
Furthermore, others have raised the
possibility of “prebiotic” relevance;
however, to date only organic solvents
have been utilized, thus diminishing the
strength of this argument.[9, 13, 14] At first
glance, these developments would be
significant advances in organocatalysis
and green chemistry. However, the reactions are not performed under truly
aqueous conditions. While each of these
reports depict enamine-catalyzed aldol
reactions in varying degrees of an aqueous environment, we focus here on the
recent findings of Hayashi and Barbas as
representative examples, as these studies directly state their reactions are
performed in water. In the spirit of
constructive dialogue, we draw attention
to particular aspects of developing
small-molecule-organocatalyzed asymmetric aldol reactions in water.
It is well established that aldol
reactions can be catalyzed by a general
base, and small-molecule aqueous catalysts were published as early as 1909.[15]
However, to promote enantioselectivity
by an enamine-based mechanism in
[*] Dr. A. P. Brogan, Prof. Dr. T. J. Dickerson,
Prof. Dr. K. D. Janda
Departments of Chemistry and Immunology
Skaggs Institute for Chemical Biology, and
Worm Institute of Research & Medicine
The Scripps Research Institute
10550 N. Torrey Pines Road, La Jolla, CA
92037 (USA)
Fax: (+ 1) 858-784-2595
[**] Comments to several reports on enaminebased organocatalysis of aldol reactions in
water (Refs. [6–12]). We thank Prof. Dale L.
Boger for helpful discussions during the
preparation of this manuscript.
Figure 1. Structures of amine catalysts used in organocatalytic aldol reactions. TBS = tertbutyldimethylsilyl; TIPS = triisopropylsilyl; TBDPS = tert-butyldiphenylsilyl; TFA = trifluoroacetic
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. 2006, 118, 8278 – 8280
water, general-base catalysis must be
minimized. Therefore, buffered conditions are a prerequisite. To our knowledge, the only research groups to have
demonstrated small-molecule enaminebased aldol reactions under buffered
aqueous conditions are those of Reymond,[16, 17] Joyce,[18] and our own.[19]
Specifically, Reymond and Chen found
that proline (7), benzylic amine 8, and a
variety of amino acids can function as
catalysts under buffered aqueous conditions, while Joyce and Oberhuber
described aldol catalysis on a DNA
template using a variety of small-molecule amines, including lysine and putrecine. We reported that nornicotine (9), a
nicotine metabolite and minor component of tobacco smoke, catalyzes aldol
reactions under buffered aqueous conditions (pH 7–8).[19] Modest asymmetric
induction was observed by using enantiopure nornicotine (20 % ee), while no
asymmetric induction was reported by
Reymond[16, 17] or Joyce.[18]
Enamine formation in water is counterintuitive (Figure 2). However, the
nornicotine–acetone enamine can be
Figure 2. Enamine formation in water.
observed in D2O by 1H NMR spectroscopy.[20] In fact, no organic solvent was
necessary for enamine formation with
nornicotine, although small amounts of
DMSO (5 %) were used to dissolve the
reactants.[19–25] Kinetic analysis verified
the presence of least one water molecule
at or before the rate-determining step of
this reaction,[20] and density functional
calculations proposed a two-step model
that utilizes a water molecule in each
high-energy transition state (Figure 3).[23] With the exception of our
own work and that of Reymond[16, 17]
and Joyce,[18] there is no direct evidence
in other reports that enamine catalysis
occurs in water.
A fundamental phenomenon overlooked by some researchers is that when
a basic compound is placed in nonbuffered water, the pH value of the
solution will increase. Catalysts 1–9 have
a primary or secondary amine necessary
for enamine-based catalysis and each of
Angew. Chem. 2006, 118, 8278 – 8280
Figure 3. Proposed mechanism for nornicotine-catalyzed aqueous aldol reaction based on
density functional calculations and kinetic isotope effect studies.
these amines has pKa 11. If catalysts 5
or 6 are placed in non-buffered water,
the pH value of the solution will increase and catalysis of the aldol reaction
will in turn be dominated by a generalbase mechanism.[26] For example, a typical procedure using catalyst 6[7] involved 50 mmol of catalyst in 1.0 mL of
water (50 mm solution of catalyst). Assuming a pKa value of 11 for 6, simple
calculations lead to a pH value of 11.8
for the reaction mixture. Catalysis observed for 5 in non-buffered water is
also attributable to general-base catalysis. Consequently, it was not until TFA
or other strong acids were added that
high diastereo- and enantioselectivities
were observed, characteristic of an enamine mechanism. Catalysts 1–4 include
a carboxylic acid in addition to the
amine and, therefore, are likely zwitterionic in water. However, Hayashi et al.
used approximately the same amount of
catalyst (60 mmol) as Barbas and coworkers reported in their study, although in much less water (0.32 mL);
in fact, there is less water than either of
the reactants (0.6 mL of benzaldehyde
and 3.1 mL of cyclohexanone).[6] Given
that there is a tenfold excess of cyclohexanone over water, cyclohexanone
should be regarded as the solvent or
the reaction should be deemed neat with
9 % water. With this amount of water,
the reaction should not be considered
aqueous. Furthermore, from a green
chemistry perspective the cyclohexanone waste is essentially organic solvent
waste unless the cyclohexanone is easily
recycled; therefore, the reaction appears
to have little green chemistry benefit.
We would argue that catalysis in any
of these reports is not really occurring in
water. The solubility of catalysts 1–3 and
6 in water at concentrations of 50 mm is
expected to be minimal given the large
hydrophobic groups that each contain.
Furthermore, when compared with the
common cationic detergent C16TAB,
which has a critical micellar concentration of 1 mm, these amphilic catalysts
are likely to form micelles at the concentrations reported. Contrary to the
title of the study by Hayashi et al., a few
drops of water does not constitute that
the reaction is performed in water (see
above).[6] Indeed, it is stated that the
reaction mixture is biphasic in the
discussion. The report by Barbas and
co-workers makes note of the limited
solubility of catalyst 6 and accurately
portrays catalysis, describing the reaction mixture as an emulsion.[7] Yet, these
reactions are not truly in water as
opposed to being isolated from water.
Conditions for catalyst 6 to provide
enantiomeric enrichment requires a stoichometric amount of TFA relative to
catalyst 6. However, the reaction then
takes approximately five times longer to
reach completion.[7] The increased reaction rate and lack of enantiomeric
enrichment without the addition of acid
suggests that catalysis in the absence of
TFA is dominated by a general-base
mechanism. As the addition of a stoichiometric amount of TFA (or any acid)
favors the formation of micelles by
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
increasing the amphiphilic character of
the catalysts, the enantiomeric enrichment observed with the addition of TFA
occurs from catalysis in what is accurately described as a “concentrated
organic phase”, whereby the hydrophobicity of catalyst 6 is concluded to
sequester the enamine intermediate
and concomitant transition state(s)
away from water.[7] The reaction is not
really in water and is likely occurring in
a micelle, resulting in the exclusion of
water and generating a formally biphasic reaction mixture.
These results can be compared to the
pioneering study by Breslow and Rideout in which the rate of a Diels–Alder
reaction was increased by performing
the reaction in water.[27] In that case,
hydrophobic molecules are forced into
close contact,[28] in contrast to recent
amine-catalyzed aldol reactions in
which the reactants are excluded from
water by the amphiphilic catalyst. Perhaps a more accurate term for these
organocatalyzed reactions in concentrated organic phases or micelles would
be the “on water” concept recently
introduced by Sharpless et al.[29] Nonetheless, the study by Hayashi et al. is not
carried out in water and the study by
Barbas and co-workers is carried out
with an emulsion. Thus, a more accurate
description should be used to delineate
these systems from truly aqueous systems.
The latest reports of enamine-based
aldol reactions in water have prompted
us to highlight some aspects in this
active topic of research. We do not wish
to diminish the significance of the enantiomeric enrichment observed in the
reports by Barbas and co-workers and
by Hayashi et al., nor do we wish to
argue against catalysis occurring in concentrated or isolated organic environments. However, there is a clear distinction between what is described in this
work and others where enamine-based
catalysis is actually occurring in a buffered milieu.[16–24] Finally, no small-molecule (MW < 600) catalysts have provided synthetically relevant enantioselectivity in aqueous buffered solution—
a hallmark of catalytic antibodies and
biologically derived catalysts such as
enzymes. We recognize the reports of
“minimal aldolases”,[30–32] yet these polypeptides cannot be considered small
molecules. Thus, a clear challenge remains: Can small-molecule catalysts be
developed to catalyze reactions in buffered solution with suitable asymmetric
Received: April 8, 2006
Online verIffentlicht am September 25, 2006
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